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    Clinical Trial Results:
    A Phase 3 Multicenter, Multi-dose, Open-label Maintenance Study to Investigate the Long-term Safety and Efficacy of ZS (Sodium Zirconium Cyclosilicate), an Oral Sorbent, in Subjects with Hyperkalemia

    Summary
    EudraCT number
    2014-004555-31
    Trial protocol
    DE   GB   NL   RO  
    Global end of trial date
    04 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    02 May 2018
    First version publication date
    02 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZS-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02163499
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ZS Pharma Inc
    Sponsor organisation address
    508 Wrangler Drive, Suite 100, Coppell, United States, 75019
    Public contact
    Astra Clinical Study Information Center, ZS Pharma Inc, 1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Astra Clinical Study Information Center, ZS Pharma Inc, 1 877-240-9479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To generate open-label, long-term (up to 12 months) safety and tolerability data for ZS in subjects with hyperkalemia (serum potassium [S-K] ≥ 5.1 mmol/L).
    Protection of trial subjects
    Stopping rules If a subject develops excessive hypokalemia or hyperkalemia defined as i STAT potassium values < 3.0 mmol/L at any time during the study or > 6.5 mmol/L at any time during the Maintenance Phase of the main study or > 6.2 mmol/L at any time during the Randomized Withdrawal Study, the subject should immediately receive appropriate medical treatment and be discontinued from investigational product. In addition, a subject who develops any of the following cardiac events will be immediately discontinued from the study (independent of whether it occurs during the Acute Phase, Maintenance Phase, or Randomized Withdrawal Study): • Serious cardiac arrhythmias (ventricular tachycardia or ventricular fibrillation, new atrial fibrillation or atrial flutter, new paroxysmal supraventricular tachycardia [other than sinus tachycardia], new 2nd or 3rd degree atrioventricular block or significant bradycardia [heart rate < 40 bpm]) • Acute congestive heart failure • Significant increase in PR interval (> 250 msec in the absence of pre-existing atrioventricular block), widening of the QRS complex (> 140 msec in the absence of pre-existing bundle branch block) or peaked T-wave, or an increase in QTc > 30 msec to more than 500 msec, > 30 msec increase in QTc in a subject with a baseline QTc of > 500 msec, or an absolute increase in QTc of > 60 msec
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 31
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 639
    Country: Number of subjects enrolled
    Australia: 52
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    751
    EEA total number of subjects
    29
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    378
    From 65 to 84 years
    345
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    751
    Number of subjects completed
    751

    Period 1
    Period 1 title
    Acute Phase
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Sodium zirconium cyclosilicate
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium zirconium cyclosilicate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    10 g TID

    Number of subjects in period 1
    Sodium zirconium cyclosilicate
    Started
    751
    Completed
    746
    Not completed
    5
         Protocol deviation
    1
         Physician decision
    1
         Participant compliance
    1
         Consent withdrawn by subject
    1
         Hypo- or hyperkalemia
    1
    Period 2
    Period 2 title
    Long term maintenance Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Sodium zirconium cyclosilicate
    Arm description
    Sodium zirconium cyclosilicate (ZS) 5 g once daily (5 g dose titrations)
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium zirconium cyclosilicate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    5 g QD

    Number of subjects in period 2
    Sodium zirconium cyclosilicate
    Started
    746
    Completed
    466
    Not completed
    280
         Protocol deviation
    2
         Met ECG withdrawal criteria
    7
         Physician decision
    8
         Various reasons
    56
         Adverse event, serious fatal
    8
         Participant compliance
    17
         Adverse event, non-fatal
    51
         Consent withdrawn by subject
    81
         Sponsor decision
    5
         Lost to follow-up
    31
         Hypo- or hyperkalemia
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Acute Phase
    Reporting group description
    -

    Reporting group values
    Acute Phase Total
    Number of subjects
    751 751
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    378 378
        From 65-84 years
    345 345
        85 years and over
    28 28
    Age Continuous
    Units: years
        median (standard deviation)
    64 ± 13.03 -
    Gender Categorical
    Units: Subjects
        Female
    303 303
        Male
    448 448

    End points

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    End points reporting groups
    Reporting group title
    Sodium zirconium cyclosilicate
    Reporting group description
    -
    Reporting group title
    Sodium zirconium cyclosilicate
    Reporting group description
    Sodium zirconium cyclosilicate (ZS) 5 g once daily (5 g dose titrations)

    Primary: Restoration of normal serum potassium (S-K) values (3.5 to 5.0 mmol/L, inclusive) at the end of the Acute Phase

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    End point title
    Restoration of normal serum potassium (S-K) values (3.5 to 5.0 mmol/L, inclusive) at the end of the Acute Phase [1]
    End point description
    Percentage of subjects with S-K values between 3.5 and 5.0 mmol/L, inclusive at the end of the Acute Phase - ITT Population
    End point type
    Primary
    End point timeframe
    72 Hours
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No extra statistical Analysis,other than confidence interval, needed as no comparison between treatment groups are being carried out
    End point values
    Sodium zirconium cyclosilicate
    Number of subjects analysed
    748
    Units: Percentage
    number (confidence interval 77.9%)
        Percentage
    77.9 (74.8 to 80.9)
    No statistical analyses for this end point

    Primary: Maintenance of normokalemia for subjects across Extended Dosing Phase Days 85 to 365

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    End point title
    Maintenance of normokalemia for subjects across Extended Dosing Phase Days 85 to 365 [2]
    End point description
    Percentage of subjects with mean S-K values ≤ 5.1 mmol/L during Extended Dosing Phase - ITT Population
    End point type
    Primary
    End point timeframe
    Study Days 85 to 365
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No extra statistical analysis required as no hypothesis being considered and you have percentage of subjects that remained Normokalemia, for the extended dosing period, togehter with a confidence interval
    End point values
    Sodium zirconium cyclosilicate
    Number of subjects analysed
    646
    Units: Percentage
    number (confidence interval 88.4%)
        Percentage
    88.4 (85.7 to 90.8)
    No statistical analyses for this end point

    Secondary: Mean S-K levels Study Days 85 to End of Study

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    End point title
    Mean S-K levels Study Days 85 to End of Study
    End point description
    Mean S-K levels months 3 to 12(EP Days 85, 113, 141, 176, 211, 239, 267, 295, 330, 365 and EOS),months 6 to 9, and months 9 to 12.
    End point type
    Secondary
    End point timeframe
    12 months and 7 days
    End point values
    Sodium zirconium cyclosilicate
    Number of subjects analysed
    734
    Units: mmol/L
    arithmetic mean (standard deviation)
        Acute Phase Baseline
    5.59 ± 0.425
        Extended Dosing Days 85 to 365/End of Study
    4.66 ± 0.379
        Extended Dosing Days 211 to 267
    4.68 ± 0.404
        Extended Dosing Days 295 to 365
    4.62 ± 0.401
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from start of first study drug medication to end of study visit which occurred +/- 7 days after last dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Induction Phase
    Reporting group description
    -

    Reporting group title
    Long term maintenance phase
    Reporting group description
    -

    Serious adverse events
    Induction Phase Long term maintenance phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 751 (0.13%)
    162 / 746 (21.72%)
         number of deaths (all causes)
    0
    8
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 751 (0.00%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension crisis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occulsive disease
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast canver
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metasases to lung
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Dependence enabling machine or device
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 751 (0.00%)
    11 / 746 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalized oedema
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug dose omission
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Troponin increased
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 751 (0.00%)
    6 / 746 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrilliation
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bundle branch block right
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 751 (0.00%)
    11 / 746 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 751 (0.00%)
    11 / 746 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart injury
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis uraemic
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 751 (0.00%)
    5 / 746 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysponea
         subjects affected / exposed
    0 / 751 (0.00%)
    5 / 746 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercapnia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerbrovascular accident
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemia attac
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorhage
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 751 (0.00%)
    8 / 746 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 751 (0.00%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 751 (0.00%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 751 (0.00%)
    2 / 746 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 751 (0.00%)
    7 / 746 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gas gangrene
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic airways disease
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 751 (0.00%)
    8 / 746 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 751 (0.00%)
    14 / 746 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 751 (0.00%)
    3 / 746 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 751 (0.13%)
    4 / 746 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 751 (0.00%)
    1 / 746 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Induction Phase Long term maintenance phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 751 (1.73%)
    354 / 746 (47.45%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 751 (0.13%)
    78 / 746 (10.46%)
         occurrences all number
    1
    94
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 751 (0.00%)
    42 / 746 (5.63%)
         occurrences all number
    0
    45
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 751 (0.13%)
    72 / 746 (9.65%)
         occurrences all number
    1
    84
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 751 (0.53%)
    56 / 746 (7.51%)
         occurrences all number
    4
    67
    Constipation
         subjects affected / exposed
    2 / 751 (0.27%)
    46 / 746 (6.17%)
         occurrences all number
    2
    53
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 751 (0.40%)
    55 / 746 (7.37%)
         occurrences all number
    3
    79
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 751 (0.00%)
    37 / 746 (4.96%)
         occurrences all number
    0
    38

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2014
    Changed the description of ZS to sodium zirconium cyclosilicate. Increased the number of subjects in the randomized withdrawal study from 120 to 200 subjects due to a US FDA request for a less sensitive power analysis. Removed the testing for fasting plasma glucose since fasting serum glucose was collected at the same time points. Modified the dose stopping rule to include the Acute Phase and changed the upper limit of the i-STAT potassium value that required discontinuation of study drug from 6.4 to 7.0 mmol/L to mirror the upper limit that was used in the recently completed Phase 3 study, ZS-003. Added details regarding the analysis of data from the randomized withdrawal study.
    16 Oct 2014
    Reduced the i-STAT potassium value requiring a dose increase of ZS to 5 g QD or 10 gQD from 5.6 to 7.0 mmol/L to 5.1 to 7.0 mmol/L. Reduced the i-STAT potassium value that required discontinuation of study drug in the randomized withdrawal study from > 7.0 mmol/L to > 6.2 mmol/L, which was consistent with the completed study, ZS-004, which had a placebo arm. Limited participation in the randomized withdrawal study to selected sites in North America rather than all study sites. Clarified that the site was to contact the Medical Monitor for dosing directions in the rare case that the i-STAT potassium value was between 3.0 to 3.4 mmol/L during the Acute Phase. Updated animal toxicity data from a 9-month oral toxicity study in dogs to support dosing in man beyond 9 months. Removed the requirement that a person who was reading a consent form to a vision-impaired non-English speaking subject be a member of the research team who was fluent in the language of the subject since it was not always possible to have members of the research team fluent in multiple languages. In most cases, study sites had access to individuals who were not members of the study team who could read the consent to the subject in the subject’s primary language and translate information between the subject and the investigator. Clarified that only sexually active women of childbearing potential were to use 2 forms of medically acceptable contraception with at least 1 being a barrier method. Removed the lower limit for room temperature storage of study drug based on ongoing stability data.
    22 Dec 2014
    Reduced the i-STAT potassium value that required a subject to stop dosing in the Extended Dosing Phase from > 7.0 mmol/L to > 6.5 mmol/L for increased safety during long-term dosing. Required subjects to return to the site 7 (± 1) days later if a RAAS inhibitor or diuretic dose was adjusted or initiated during the Extended Dosing Phase or randomized withdrawal study to measure potassium since changes in either of these medications may have altered the level of blood potassium. The i-STAT potassium value was to be evaluated, and the dose of ZS was adjusted or stopped based on the rules in the protocol. Clarified that all Extended Dosing Phase visits from Day 8 onwards may have taken place either 1 day early or 1 day late to provide greater flexibility with scheduling. Removed the requirement for the randomized withdrawal study to start when the first subject on Extended Dosing Phase Day 176 met the criteria for entry in the randomized withdrawal study. Changed the lower limit of age of an eligible subject from 19 to 18 years of age. Added the collection of blood samples for analysis of zirconium at baseline and on the morning of Acute Phase Day 2 as recommended by the US FDA at selected study sites in North America. Added additional sampling time points for the collection of blood for aldosterone and renin on Extended Dosing Phase Days 29 and 267. Modified secondary and exploratory endpoints and a secondary objective. Removed information from nonclinical studies that was available in the Investigator’s Brochure. Deleted the collection of urine for p-cresol and indole at all time points and deleted the collection of blood for BNP and galectin-3 at all time points except baseline (Acute Phase Day 1)
    18 Feb 2015
    Increased the enrollment in the Extended Dosing Phase from 500 to 750 subjects to allow sites in Europe sufficient opportunity to enroll subjects in the study. Allowed the Medical Monitor to request a dose adjustment based on the central laboratory potassium value and not the i-STAT value if there was a significant discrepancy between the values. This was to be determined on a case-by-case basis by the Medical Monitor. Dose escalation was still only requested if central laboratory S-K value was > 5.0 mmol/L (increase from 5 g QOD to 5 g QD or increase from 5 to 10 g QD) or > 5.5 mmol/L (increase from 10 to 15 g QD). Defined medically acceptable contraception as requested by the Clinical Trials Facilitation Group in the European Union as part of the Voluntary Harmonization Procedure assessment.
    11 Mar 2015
    Added clarification of medically acceptable contraception methods to Inclusion Criterion 5.
    29 Apr 2015
    Incorporated the use of a lower volume of water (40 mL with no mandatory rinses) to deliver the study drug for subjects who enrolled in the trial under this amendment at selected sites in the US. All other subjects were to continue to use 180 mL plus 2 mandatory rinses of 30 mL each to deliver the study drug. This allowed for the collection of safety and tolerability data of the study drug using a lower volume of water. Subjects who enrolled in the study under this amendment at selected sites in the US received a dosing card that provided detailed written directions for proper preparation of study drug doses. If a subject who should have consumed ZS using 40 mL of water with no mandatory rinses mistakenly used 180 mL of water followed by two 30 mL rinses, this was to be recorded on the subject’s dosing card and in EDC as a deviation and accounted for during data analysis. Added 2 new secondary endpoints and modified an exploratory endpoint. Incorporated all country-specific wording, thereby eliminating the need for any country-specific amendments. Specified that expected progression of CKD requiring dialysis, transplant or other treatment resulting in study discontinuation was not to be reported as an adverse event in this trial. The event was to be reported on the End of Study eCRF in EDC. Removed the requirement that the independent Data Monitoring Committee (iDMC). review data on an ongoing basis for this study. The ZS Pharma Medical Monitor continued to monitor safety data throughout the study.
    02 Feb 2016
    Removed the randomized withdrawal study from the trial. Emerging data from ZS-005 consistently showed that once treatment was stopped (on Day 365), S-K values returned into the hyperkalemic range. In addition, interim data from Study ZS-005 very clearly demonstrated that ZS maintained normokalemia in 90 to 100% of the subjects with a mean S-K value of 4.6 mmol/L. Changed the title of the protocol due to removal of the randomized withdrawal study from the trial. Clarified that subjects who had a history of heart failure were classified according to the New York Heart Association functional classification system. Clarified that adverse events were collected for 7 (± 1) days after the last dose of study drug which corresponded with the acceptable time frame of the End of Study visit. Clarified that expected progression of CKD requiring dialysis, transplant, or other treatment resulting in study discontinuation not related to ZS was not to be reported as an adverse event or serious adverse event.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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